JP4917738B2 - Solid galenical formulation for administration of active ingredients to the eye, solid and soluble eye insert and method of making the insert - Google Patents

Abstract

Ocular insert comprises a solid shape (I) for ocular administration of an active agent comprising at least one water soluble and ophthalmologically biocompatible excipient (II). The shape is obtained by compression or freeze drying so that it can be contained in the conjunctival sac.

Description

The present invention relates to a solid galenical formulation for administering an active ingredient to the eye, an insert obtained from the formulation for use in a solid and soluble eye, and a method for producing such an insert.
The galenical formulations of the present invention can be used interchangeably in human medicine or veterinary medicine to obtain local or systemic effects.

A number of pharmacological compositions are used for the purpose of treating eye disorders. These compositions are generally in liquid, gel or ointment form. Due to the secretion or excretion of tears, these preparations cannot ensure a sufficient contact time at the corneal level sufficient to allow the active ingredient to penetrate sufficiently.
Since 1973, an insert-type, dried solid formulation has been proposed for placement in the conjunctival sac. These inserts generally comprise an insoluble polymer matrix for releasing and releasing the active ingredient over an extended period of time. It is therefore necessary to remove them from the conjunctival sac after a sufficient contact time. In particular, the use of such a formulation is indicated when the prescribed treatment is for a long period of time or when a long-term contact is required. The use of this type of insert is also being studied for the purpose of administering an exact dose of an active ingredient.

Such insoluble inserts have the disadvantage that they slowly release the active ingredient, optionally retained in the matrix. Similarly, its use may be inconvenient if it requires rapid action.
Because of this insoluble matrix, it is necessary to increase the dose of the active ingredient and its release profile is not always regulated. This is because the polymer matrix does not release a predetermined amount of active ingredient. Another disadvantage of these formulations is that they need to be removed after use, which can destroy the insert at the time of retreatment.

Biodegradable and soluble ophthalmic inserts were made from water soluble and biodegradable polymers. These inserts are likewise for achieving long-term and controlled release of the drug substance by dissolving or slightly or steppingly swelling the used polymer.
US-A-4,179,497 discloses an ophthalmic insert based on a hydroxypropylcellulose (HPC) matrix, containing pilocarpine and made by an extrusion or heat compression molding process. These inserts obtained using the thermoplastic properties of HPC are soft and flexible after compression. When administered to the eye, they soften and then dissolve slowly. When heated, the active ingredients sensitive to heat may be decomposed.

Accordingly, it is desirable to provide a solid galenical formulation for administering the active ingredient to the eye that allows for rapid release of the active ingredient.
Similarly, it provides a solid galenical formulation for administering the active ingredient to the eye that allows controlled release, as well as a soluble ophthalmic insert that can release the active ingredient in a rapid and controlled manner It is desirable to do.
In general, it is desirable to always limit the total number of components to the maximum, due to issues such as cost or interactions between different components.

  This is the main reason why the present invention seeks to provide a solid galenical formulation for administering the active ingredient of the present invention to the eye, the galenical formulation being at least one ophthalmic water-soluble and biological Characterized in that it contains a compatible excipient and is made by a method selected from the group consisting of compression and lyophilization so that the active ingredient can be released into the conjunctival sac. A solid galenical formulation for administration to the eye, comprising at least one ophthalmic water-soluble and biocompatible excipient so that the active ingredient can be released into the conjunctival sac , Direct compression, dry compression, wet compression, lyophilized product compression, wherein the compression is performed at a temperature of 45 ° C. or less, and is obtained by any method of lyophilization.

This galenical formulation according to the invention is dry and hard.
The term “active ingredient” is not limited to a compound having a pharmacological action in the meaning used in the present invention, but has no pharmacological action, but has a physical or mechanical action. Also meant are compounds that can be used as such.
The term “water-soluble” means that the excipient dissolves directly or partially in water without going through a gel state.
The water-soluble and biodegradable excipient for ophthalmic use is advantageously selected from the group consisting of water-soluble polymers.
The water-soluble and biodegradable excipients include, for example, carbohydrates, gums, sodium salts, calcium salts, magnesium salts, malt dextrin, cellulose derivatives, chitosan, decomposed amidone, partially hydrolyzed amidone, cross-linked amidone, polyvinyl alcohol and acrylic. Selected from the group consisting of acid polymers.

The cellulose derivative is preferably selected from hydroxyalkylcelluloses such as hydroxypropylcellulose.
The water-soluble and biodegradable excipient has a concentration reaching 99.9% by weight, preferably in the range from about 40 to about 99.5% by weight, in particular in the range from 50 to 99% by weight and especially in the range from 60 to 95% by weight. May be present in concentration.
According to the present invention, the galenical formulation further comprises excipients known in ophthalmic formulations selected from the group consisting of soluble lubricants, disintegrants, expelling agents, polymer coatings, and binders. Can do.
The soluble lubricant is selected from the group consisting of, for example, sugar esters, polyethylene glycol, leucine and sodium borate.
The disintegrant is selected, for example, from the group consisting of cellulose derivatives, sodium croscarmellose, crospovidone and povidone.
The cellulose derivative is, for example, sodium carboxymethyl cellulose.

The polymer coating is generally selected from thermoplastic derivatives of cellulose. The thermoplastic derivatives of cellulose are, for example, ethyl cellulose and cellulose acetate. They need to be soluble in tears.
The number of excipients contained in the galenical formulation according to the invention is advantageously 5 or less, preferably 4 or less, in particular 3 or less, in particular only one excipient.
In advantageous conditions for practicing the present invention, the above-mentioned galenical preparation is substantially free of plasticizers such as polyethylene glycol, glycerin or hydroxypropyl sucrose.
In other advantageous conditions for practicing the present invention, the galenical formulation described above is substantially free of preservatives.
“Substantially free” means that the mass-based amount of the compound in question is 1% or less, in particular 0.5% or less, of the total mass of the final formulation. Under these conditions, the substance in question is particularly preferably absent from the galenical preparation.

The galenical preparation of the present invention may further contain a pharmacologically active substance or a substance that is pharmacologically inactive but has, for example, a physical or mechanical action.
The pharmacologically active substance includes, for example, anesthetic agents such as tetracaine, lidocaine or bupivacaine, anti-allergic agents such as sodium cromoglycate, corticoid anti-inflammatory agents such as dexamethasone sulfate or other salts of dexamethasone, Non-steroidal anti-inflammatory agents such as diclofenac, indomethacin, or ibuprofen, antibiotics such as gentamicin or tobramycin, antibiotics or anti-viral agents such as acyclovir or ganciclovir, mydriatics such as phenylephrine, tropicamide, atropine, Selected from the group consisting of anti-glaucoma drugs such as pilocarpine, timolol, prostaglandins. In addition, antiseptics such as cyclosporine, healing agents, diagnostic substances, tear replacement agents, vasoconstrictors, miotic agents, anti-fungal agents, and anti-inflammatory agents can also be exemplified.
The pharmacologically active substance can be selected from an action based on a local viewpoint or an action based on a systemic viewpoint.

The pharmacologically inert substance can be, for example, hydroxypropylcellulose, allowing the treatment of dry eye syndrome.
Those skilled in the art will readily determine the amount of the pharmacologically active substance as a function of the properties of the substance and the predetermined therapeutic effect.
The galenical formulations of the present invention are advantageously sterilized and conditioned for single or multiple administration, preferably in devices that simplify administration.
The performance of this or these excipients and the method, for example the compressive force, is advantageously determined by the person skilled in the art to the galenical formulation according to the invention in 2 hours or less, preferably 1 hour or less, in particular 45 minutes or less, in particular 30 It will be chosen to give a decay time of less than a minute, more specifically less than 15 minutes. This collapse can be, for example, 2 minutes.
For example, when a disintegrant is added, this disintegration period can be shortened.

The above-mentioned solid galenical preparation for administration to the eye of the present invention has very interesting physical properties. These in particular allow a rapid release of one or more active ingredients. They also allow controlled release of these active ingredients.
These characteristics are illustrated in the experimental part below. The following examples demonstrate the use of the solid galenical formulation for administration to the eye, specifically described above as carrying a drug.
The solid galenical formulation for administration to the eye according to the present invention finds use in, for example, the treatment and prevention of eye inflammation, dry eye syndrome, allergic symptoms of the eye, and anesthesia.
The galenic formulation of the present invention can be used without distinction for the purpose of local or systemic action in human medicine or veterinary medicine.
This is the reason why the present invention aims to provide an ophthalmic insert which is composed of the above-described galenical preparation and has dimensions suitable for administration to the eye.

The galenical preparation constituting the ophthalmic insert is characterized by having a length in the range of about 1 mm to about 10 mm, for example in the range of about 2 mm to about 5 mm for an elongated insert. Circular inserts will have a diameter, for example up to about 10 mm, in particular in the range of about 1 to about 4 mm.
The galenical formulation of the present invention can be produced in particular by the following method:
・ Direct compression method,
・ Dry compression method,
・ Wet compression method and ・ Compression method of freeze-dried product. In order to prepare a lyophilizate based on a mixture, in particular an equal mixture of active ingredient and mannitol, this lyophilisate and, for example, hydroxypropylcellulose and PEG 6000 are preferably mixed after homogenization. The whole can be mixed with an excipient for direct compression such as mannitol and compressed with an appropriate mold to obtain the freeze-dried product.

In order to make the galenical formulation of the present invention, it can be treated in particular as follows:
(a) Sifting the mixture of various ingredients in powder form and the direct compression product of this mixture, possible active ingredients and excipients with a mesh sieve generally ranging from about 0.100 to 0.630 mm . Prior to direct compression, wetting agents such as hyaluronic acid, lubricants, etc. are added, or lactose, sugar, or sucrose, such as microcrystals (Microcristal 120 ^™ ) or compressacs (Compressuc ^™ with various particle sizes). ) And the like can be prepared.
(b) Complete or partial granulation or coating of the excipients and compacts.
(c) The active ingredient is dissolved in a solvent, for example an aqueous solution or saline, preferably a solution based on an equivalent such as mannitol or sorbitol, and then the solvent is evaporated according to a lyophilization technique.

This compression is carried out at 45 ° C. or lower, preferably 35 ° C. or lower, especially 30 or lower, especially 25 ° C. or lower, and especially at ambient temperature.
In some cases, the process can also be performed under cooling conditions (eg, 4 ° C.) to avoid the possibility of decomposition when the active ingredient is thermally unstable. Is possible.
The above preferred conditions for using the galenical formulation for administration to the eye apply as well as the other objects of the invention shown below.
In short, the present invention is a solid galenical formulation comprising at least one ophthalmic water-soluble and biocompatible excipient, and produced by the above method so as to release the active ingredient to the conjunctival sac. It is also intended to be used for administering the active ingredient to the eye.

The invention will now be illustrated by the following examples.
Example 1
A galenical formulation of the present invention in the form of an ophthalmic insert containing tetracaine hydrochloride as a pharmacologically active substance, formulated in a powder mixture, obtained from the ingredients shown in Table 1 below is prepared.

The lactose for direct compression used is lactose marketed by the company BASF under the name Ludipress ^™ LCE.
These active ingredients and excipients are sieved through a 0.400 mm mesh sieve. They are then weighed and mixed for 5-10 minutes.
The ophthalmic insert is then obtained by directly compressing the mixture thus obtained with a rotating device comprising twelve elongated molds having a length of 4.3 mm and a width of 2.3 mm.
The dissolution time of the ophthalmic insert thus obtained is 4 minutes.
Example 2
A galenical formulation is prepared from the ingredients listed in Table 2 below according to the same procedure as in Example 1.

The lactose for direct compression used is lactose marketed by the company BASF under the name Ludipress ^™ LCE.
The crospovidone used as a disintegrant is commercially available from Basf under the name Kollidon ^™ CL-M.
An ophthalmic insert is obtained in the same manner as in Example 1.
The dissolution time of the ophthalmic insert thus obtained is 2.5 minutes.
Example 3
A galenical formulation is prepared from the ingredients listed in Table 3 below according to the same procedure as in Example 1.

The lactose for direct compression used is lactose marketed by the company Basf under the name Ludipress ^™ .
An ophthalmic insert is obtained as described in Example 1 or 2.
The dissolution time of the ophthalmic insert thus obtained is 4.5 minutes.
Example 4
A galenical formulation is prepared from the components listed in Table 4 below according to the same procedure as in Example 1.

The lactose for direct compression used is lactose marketed by the company Basfu under the name Ludipress ^™ LCE.
An ophthalmic insert is obtained as described in Example 1 or 2.
The dissolution time of the ophthalmic insert thus obtained is 2 minutes.
Example 5
A galenical formulation is prepared from the components listed in Table 5 below according to the same procedure as in Example 1.

The lactose for direct compression used is lactose marketed by the company Basfu under the name Ludipress ^™ LCE.
An ophthalmic insert is obtained as described in Example 1 or 2.
The dissolution time of the ophthalmic insert thus obtained is 3 minutes.
Example 6
According to the same operation as in Example 1, a galenical preparation is prepared from the components listed in Table 6 below.

The lactose for direct compression used is lactose marketed by the company Basfu under the name Ludipress ^™ LCE.
An ophthalmic insert is obtained as described in Example 1 or 2.
The dissolution time of the ophthalmic insert thus obtained is 4 minutes 50 seconds.
Although similar active ingredients, anesthetics, were used alone to allow comparison of dissolution times, any active ingredient available for ophthalmology can be incorporated into the compositions of the present invention. Is obvious.
Example 7
A galenical formulation is prepared according to the present invention from the ingredients listed in Table 7 below.

A lyophilized product based on an equal mixture of active ingredient (lactoferrin) and mannitol is obtained, homogenized, and this homogenized mixture is mixed with HPC and PEG 6000, which is combined with mannitol for direct compression. In order to mix and obtain an insert according to the invention, compression and first and second conditioning are performed.
The resulting ophthalmic insert is a galenical formulation with an average mass of 12 mg and a fracture resistance (in hardness tests according to the European Pharmacopoeia, the hardness was estimated to be 40 N).
The mannitol for direct compression is added to improve the coverage of the powder and to obtain an excellent compressed product of the resulting lyophilized product mixture.
Example 8: Galen formulation prepared by compression after granulation by a wet method From the components listed in Table 8 below, a galenic formulation is prepared.

Diclofenac and the first part of HPMC are mixed, wet granulated with a water / ethyl alcohol mixture, dried at 42 ° C. for 2 hours, sieved, sieved, and the granules of HPMC. Mix with the second part, add the lactose for direct compression, compress 500 g of the resulting granule to obtain a composite with an average mass of 12 mg and release over 1 hour 30 minutes.
By changing the proportion of the above components, the dissolution time of the resulting insert can be changed. This time can be in the range of about 20 minutes, optionally 1 hour 30 minutes to 2 hours, but 8 hours can also be achieved, rather the release time can be in the range of 12 to 24 hours.
Example 9: Galen formulation prepared by compression after granulation by a wet method From the components described in Table 9 below, a galenic formulation is prepared.

  Diclofenac and HPMC were mixed, then leucine (manufactured by Fluka) and leucine (manufactured by Sigma) were added, and the resulting mixture was subjected to wet granulation using a water / ethyl alcohol mixture. The granules are dried at 42 ° C. for 2 hours, sieved, the resulting granules are mixed with the remaining leucine for the outer layer, and lactose for direct compression is added thereto to adjust the compression force. The resulting granules 500 g were compressed to obtain an ophthalmic insert with an average mass of 12 mg, which can release diclofenac over at least 8 hours.

Claims (17)

A solid galenical formulation for administering an active ingredient to the eye,
Comprising at least one ophthalmic water-soluble and biocompatible excipient;
The water-soluble and biocompatible excipient is present at a concentration in the range of 40-99.5% by weight ;
The water-soluble and biocompatible excipient comprises at least one selected from the group consisting of lactose and mannitol ;
Direct compression,
・ Dry compression,
・ Wet compression,
Compression of the lyophilizate, where the compression is performed at a temperature of 45 ° C. or lower,
-It must have been obtained by any method of lyophilization,
The solid galenical preparation described above, wherein the preparation is disintegrated and the active ingredient can be released into the conjunctival sac within 2 hours. The solid galenical formulation according to claim 1, wherein the water-soluble and biocompatible excipient further comprises a first cellulose derivative. The first cellulose derivative is selected from the group consisting of hydroxyalkyl cellulose, solid galenic formulation according to claim 2. The first cellulose derivative is hydroxypropyl cellulose, solid galenic formulation according to claim 2. Furthermore, at least 1 type of excipient | filler selected from the group which consists of a soluble lubricant, a disintegrating agent, a discharge agent, a polymer coating agent, and a binder is also included in any one of Claims 1-4 . Solid galenical formulation. The solid galenical preparation according to any one of claims 1 to 5 , further comprising at least one soluble lubricant selected from the group consisting of sugar ester, polyethylene glycol, leucine and sodium borate. Furthermore, at least 1 sort of disintegrating agent selected from the group which consists of a 2nd cellulose derivative, sodium croscarmellose (croscarmellose), crospovidone, and povidone is also included in any one of Claims 1-6. Solid galenical formulation. The solid galenical preparation according to claim 7 , wherein the second cellulose derivative is sodium carboxymethylcellulose. The solid galenical preparation according to any one of claims 1 to 8 , further comprising at least one polymer coating selected from the group consisting of thermoplastic derivatives of cellulose. The solid galenical preparation according to any one of claims 1 to 9 , further comprising at least one thermoplastic derivative of cellulose selected from the group consisting of ethyl cellulose and cellulose acetate. The solid galenical preparation according to any one of claims 1 to 10 , comprising an active pharmacological substance. 12. The solid galenical formulation according to claim 11, wherein the active pharmacological substance is selected for local action. 12. A solid galenical formulation according to claim 11, wherein the active pharmacological substance is selected for systemic action. The solid galenical preparation according to any one of claims 1 to 13 , which is sterilized and prepared for single or multiple administration. 15. An ophthalmic insert comprising the galenical preparation according to any one of claims 1 to 14 , wherein the galenical preparation has dimensions suitable for administration to the eye. insert. 16. The insert according to claim 15, wherein the galenical formulation has a length in the range of 1 mm to 10 mm or a diameter of up to 10 mm. 17. Insert according to claim 15 or 16, wherein the galenical preparation has a length in the range of 2 mm to 5 mm or a diameter in the range of 1 mm to 4 mm.